Creation: US 221 was created nationally in 1930, but didn't appear in South Carolina until 1932. It ran from NC above Cowpens Battlefield to Greenwood.
US 221 was routed from the state line down to SC 11 on today's US 221 ALT, then jogged west to Chesnee. From there, US 221 followed today's 221 through Spartanburg, Woodruff, Laurens, Waterloo, then proceeded into downtown Greenwood to end at US 25-178. This was all a renumbering of SC 10 except from Waterloo to SC 7 (current SC 72) was the original SC 72.
Adjustments:In 1941, US 221's approach to North Carolina was changed to run due north from Chesnee, replacing the original SC 110. The old route became US 221 ALT, as it remains today.
In 1954, US 221 was extended south to Bradley and McCormick, then south to the new Clarks Hill Dam into Georgia. Greenwood to Bradley was a replacement for SC 10, while Bradley to McCormick was a replacement for part of SC 670.
Between 1962-64, US 221 was given its Roebuck bypass, leaving behind S-42-425, S-42-400, and a little bit of SC 215.
Between 1968-70, US 221 was rerouted onto the Greenwood Bypass and its current routing south of US 25-178 to Bradley. This replaced the last remaining piece of SC 670. The old route through Greenwood and Verdery became SC 72 Business and a re-extended SC 10.
Improvements: Fully paved upon designation, except from Laurens to Waterloo, which was paved in 1933.
The first multilane sections of US 221 were in place between 1962-64: parts of Church St north of US 29, and from the Fairforest Creek Bridge south to I-26.
The next sections to be upgraded were to make all of Church St in Spartanburg 4-lane, and a short segment at the Greenwood bypass on the SC 72 multiplex, both between 1968-70.
In 1973, US 221 was 4-laned from Spartanburg north to I-85.
Between 1980-82, US 221 was 4-laned from I-85 north to Chesnee, and along the entire SC 72 multiplex.
Between 1998-2000, US 221 was 4-laned from I-26 south to Woodruff.
Comment: US 221 in South Carolina is not so exciting compared to its routing in North Carolina, where it is the poor man's Blue Ridge Parkway. US 221 is especially quiet south of Greenwood.
I have a 1980's Gousha atlas that misidentifies this as US 122.

Creation: US 221 ALT was created in 1941 as a renumbering of mainline US 221, running the way it does now.
Adjustments:None.
Improvements: Fully paved upon designation; no multilane segments.
Comment: US 221 ALT serves a few communities in North Carolina, but doesn't serve much purpose as an alternate to through US 221 traffic.
US 221 ALT was once part of today's SC 10.